Over the years, accumulating evidence has demonstrated a strong correlation between physicochemical properties of the extracellular matrix (ECM) and various diseases such as cancer metastasis and fibrotic pathogenesis. These emerging evidences establish that the ECM is not just a passive structural support as previously thought, but is rather an active modulator of cellular behaviors contributing to disease progression when negatively perturbed. However, a detailed understanding of the role of ECM signaling on cancer metastasis and fibrotic plaque formation and how this can be controlled for a therapeutic intervention is currently lacking. Paralleling our efforts in stem cell engineering, we are developing various platforms and systems to understand the role of physical constrains exerted by the ECM on cancer metastasis and fibrosis and the potential of using ECM as therapeutic target.
Tumor growth and metastasis: Metastatic dissemination of cancer cells is a key contributor to >90% of cancer-related mortality. Though metastasis involves multiple steps, the ability of cancer cells to break through the basement membrane and traverse through the extracellular matrix (ECM) is a crucial manifestation of cancer malignancy. Recent studies suggest that cancer cells can invade matrices in either a protease-independent or a protease-dependent manner. An emerging critical component that influences the mode of cell invasion is the physical properties of the ECM, which include porosity, alignment, and stiffness. We are developing in vitro platforms like single cell invasion assay, cancer-on-chip, tumor-associated microenvironment (TAM), etc. to study the role of ECM properties on protease mediated cancer cell migration and identifying the molecular pathways that contribute to MMP (e.g., MT1-MMP) trafficking responding to changes in the ECM. We are also employing these tools to study T cell infiltration into tumor and the role of TAM on cell recruitment.
Fibrosis: Fibrosis, the accumulation of excessive and disordered extracellular matrices (ECMs), is a pathological feature of many diseases leading to organ scarring and failure. Fibrosis affects most organs and contributes to approximately one third of natural deaths worldwide. Fibrosis appears to usurp a normal wound healing response in which fibroblast activation and deposition of a controlled amount of ECM and its remodeling are required for the proper repair of damaged tissues. An altered wound healing response, characterized by aberrant and sustained activation of fibroblasts, often leads to fibrosis. Although the underlying mechanisms are mostly unknown, altered physicochemical properties of the ECM has been considered as a contributor to fibrosis, rather than merely a manifestation of the disease. Employing transgenic mouse models and in vitro tools, we are examining the key molecular players that contribute to fibrogenesis using skin and lung as model systems.